Prosthesis Seals and Methods for Sealing an Expandable Prosthesis

ABSTRACT

Embodiments of the present disclosure are related to devices and techniques for para-valve sealing of an expandable stent-valve implanted using a catheter. In some embodiments, a stent-valve is provided which comprises a seal sleeve/cuff containing material that swells when contacted by blood. A piercing tool may be included and used to permit a user to puncture the sleeve/cuff prior to introduction into a patient&#39;s body. In some embodiments, the sleeve/cuff has an integral tubular structure configured to withstand balloon expansion of the stent-valve during or after implantation.

RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. §119(e) of U.S.provisional patent application No. 61/779,744, entitled, “ProsthesisSeals and Methods for Sealing and Expandable Prosthesis”, filed on Mar.13, 2013, the entire disclosure of which is herein incorporated byreference.

FIELD OF THE DISCLOSURE

The present disclosure relates to the field of stents implantable in thebody. Embodiments have been devised to address problems encountered inthe field of stent-valves, for example cardiac stent-valves (e.g.,prosthetic heart valves). However, the concepts disclosed herein mayhave broader application to any stent or stented prosthesis where a sealis desired at an exterior surface of a stent.

BACKGROUND OF THE DISCLOSURE

Transcatheter valve implantation (for example, transcatheter aorticvalve implantation (TAVI)) is an evolving technology for replacementvalve therapy that (i) avoids the trauma of conventional open-chestsurgery, and (ii) avoids the need for heart and lung bypass. In such atechnique, a stent-valve is compressed and loaded into a deliverycatheter. The delivery catheter is introduced to the desired site ofimplantation (for example at the heart) via a percutaneous route or viaminimally invasive surgery. The stent-valve is expanded into theimplantation position from or by the delivery catheter, and the deliverycatheter is then withdrawn.

Despite the successes of transcatheter stent-valves, technologicalchallenges remain. One such challenge is preventing retrograde leakageof blood around the stent-valve (so called para-valve leakage). Theabove-noted stents form a friction fit with the native anatomy to anchorthe stent-valve in position, and are round in cross-section. However thenative anatomy in which the stent is implanted is often off-round and isdifferent for each person. Moreover, heavy calcification of the nativeanatomy may obstruct full deployment of any stent and make the nativeanatomy even more irregular. Thus, it can sometimes be difficult toprovide a perfectly sealing fit between the stent-valve and thesurrounding anatomy. Para-valve leakage is believed to be one of thefactors affecting the long-term efficacy of the prosthetic valve, andpossibly the life expectancy of the patient. One explanation is that theheart may have to work harder to compensate for some blood leakingretrograde at the entrance or exit of the heart. Therefore, addressingpara-valve leakage is a significant challenge.

It is known to incorporate an external skirt or cover as part of thestent-valve. For example, the skirt is made of compressiblebiocompatible material, such as pericardial tissue or PET. The thickerthe material of the skirt, the more able the skirt is to occlude gapsand effect a seal. However, a disadvantage is that such skirts add tothe bulk of the stent-valve. A thick skirt makes the stent-valveproblematic to compress to a desirably small size for implantation.

US-A-2005/0137688 is understood to describe compliant sacs disposedaround the exterior of a stent, that are said to provide a moreefficient seal along an irregular interface. The sacs may be filled withan appropriate material, for example, water, blood, foam or a hydrogel.Different arrangements of sacs are proposed in principle, but thisdocument neither describes any specific construction technique nor doesit describe handling of the fill material.

U.S. Pat. No. 5,769,882 is understood to describe an implantableexpansible tubular vascular prosthesis carrying a form-in-place sealinglayer for occluding at least a circumferential band at the interfacebetween the prosthesis and the native tissue wall. In one example, thesealing layer comprises a hydrogel, arranged in a sleeve/cuff comprisinga permeable membrane.

EP 1262201 is understood to describe an implantable vascular devicehaving an external seal structure comprising a swellable hydrogel. Inuse, the hydrogel absorbs a mass of liquid so as to assume, as a resultof the absorption, a certain degree of mechanical consistency. Anexample hydrogel has a polyvinyl alcohol (PVA) base, in combination witha polysaccharide.

WO-A-2008/070442 is understood to describe prosthetic heart valves, bothexpanding and non-expanding types, each having an anchoring sleeve thatchanges shape when the valve is implanted, to prevent migration of thevalve. The anchoring sleeve is at least partly made of a material thatswells due to absorption of body fluids. In examples, the sleeve is madeof an inner material that swells upon contact with body fluids, andenclosed by a cover.

US-A-2007/0060998 and WO-A-2010/083558 are understood to describedelivery of a dispensable or releasable reactive sealing agent forendoluminal use around (at least substantially around) a prostheticdevice within a body lumen. The reactive sealing agent is released ordispensed into a space between the prosthetic device and the lumen wall,in response to exertion of a dispensing pressure or by a configurationchange causing the release. While different arrangements of dispensingcapsules are proposed, reliable containment of the agent when theprosthesis is implanted at the heart likely are not ensured, especiallyin view of the constant movement and cyclic compression experienced byheart valves.

Accordingly, it would be desirable to address one or more of the aboveissues and/or provide a technique for mitigating para-valve (orpara-stent) leakage without substantially affecting other desirablecharacteristics.

SUMMARY OF SOME OF THE EMBODIMENTS

The following disclosure presents a summary of the invention in order toprovide a basic, non-limiting, understanding of some embodiments of theinvention.

For example, in some embodiments of the present disclosure, a seal isprovided for a prosthesis. The seal may be configured for obstructingpara-prosthesis leakage. The prosthesis may, for example be astent-valve (for example a cardiac stent-valve, such as an aorticstent-valve). The seal may comprise one or any combination of two ormore of the following features, which are all optional. The list ofoptional features is bulleted by dashes (“-”).

-   -   In some embodiments, the seal is provided as a separate item        from the prosthesis. The separate seal may be mountable on the        prosthesis prior to implantation of the prosthesis. For example,        the seal may be mountable on the prosthesis as part of a        pre-implantation preparation process.    -   Alternatively, the seal may be provided as an integral part of        the prosthesis.    -   Alternatively, a flowable seal material may be introduced into a        seal sleeve or sleeve/cuff as part of a pre-implantation        preparation process.    -   A pre-implantation preparation process may, for example, be        carried out at the same hospital or clinic as the implantation        procedure and/or within 2 hours or less before the implantation        procedure (optionally about 90 minutes or less, optionally about        80 minutes or less, optionally about 70 minutes or less,        optionally about 60 minutes or less, optionally about 50 minutes        or less, optionally about 40 minutes or less, optionally about        30 minutes or less, optionally about 20 minutes or less,        optionally about 10 minutes or less).    -   A pre-implantation preparation process may comprise a step of        rinsing the prosthesis substantially clean of a storage solution        in which the prosthesis is stored and/or provided. The step of        mounting the seal on the prosthesis (if this step is        implemented) may be carried out after the prosthesis rinsing        step.

Continuing from the above list, the seal may comprise one or anycombination of two or more of the following features, as well as theabove-noted features, which are all optional:

-   -   The seal may comprise a swellable material that swells in        response to contact with blood.    -   The seal may comprise a hollow sleeve and/or hollow cuff for        containing the swellable material. The term “cuff” may refer to        the intended arrangement of the seal around the prosthesis (for        example, after mounting in the case of the mountable separate        seal, or as provided when integral with the prosthesis).        Throughout this specification the terms “sleeve/cuff” and        “cuff/sleeve” are used to mean “sleeve and/or cuff” whether or        not the “and/or” language is recited explicitly.    -   The sleeve/cuff may confine the swellable material captive        within the sleeve/cuff. In some embodiments, the swellable        material may be introduced into the sleeve/cuff during        manufacture, and provided as a sleeve/cuff containing the        swellable material. In other embodiments, the swellable material        may be introducible into the sleeve/cuff as part of a        pre-implantation preparation process (for example, as explained        above, whether or not the seal is a mountable separate seal). In        some embodiments, the swellable material is introducible by        injecting into the interior of the sleeve/cuff (for example,        injecting through the wall of the sleeve/cuff or through a        dedicated port of the sleeve/cuff).    -   The sleeve/cuff may extend generally in a circumferential        direction. In the case of a mountable separate seal, the        sleeve/cuff may extend generally in a circumferential direction        at least once mounted on the prosthesis.    -   The sleeve/cuff may define a single hollow interior space for        swellable material, or the sleeve/cuff may be partitioned to        define plural pockets or compartments for the swellable        material. At least some of the pockets may communicate with each        other, and/or at least some of the pockets may be closed spaces        not in communication with any other pocket. In some embodiments,        the internal partitioning may substantially prevent        redistribution of the swellable material between pockets, or        alternatively permit substantially free redistribution of the        swellable material between pockets, or alternatively permit        restricted redistribution of the swellable material between        pockets. In some embodiments, the internal partitioning may be        frangible so as to permit communication between two closed        pockets upon rupture of the internal partitioning.    -   The sleeve/cuff may comprise a single wall, or the sleeve/cuff        may comprise plural walls nested one behind, or within, another.        At least one wall may comprise a single layer of material,        and/or at least one wall may comprise plural layers of material        (e.g. a multi-layered wall and/or a laminate).    -   The sleeve and/or cuff, or at least a wall or layer thereof, may        comprise a region that is permeable or at least semi-permeable        to liquid. The permeable/semi-permeable region may be configured        to (i) allow communication of blood components therethrough (for        example, into the interior of the sleeve/cuff to cause the        swellable material to swell), and/or (ii) obstruct passage        therethrough of blood emboli (for example, to substantially        prevent escape into the blood stream of any emboli that may form        within the sleeve/cuff), and/or (iii) obstruct passage        therethrough of swellable material particles (for example, to        substantially prevent escape into the blood stream of any loose        particles of the swellable material).

The permeable/semi-permeable region may have pores (e.g. perforations).The pore size (e.g. average pore size) may, for example, be notsubstantially greater than about 0.2 mm. Optionally, the pore size maybe not substantially greater than about 0.15 mm, optionally notsubstantially greater than about 0.12 mm, optionally not substantiallygreater than about 0.11 mm, optionally not substantially greater thanabout 0.1 mm, optionally about 0.1 mm.

In some embodiments, the permeable/semi-permeable region may be a layerof the sleeve/cuff.

In some embodiments, the permeable/semi-permeable region may extend overonly a portion of the sleeve/cuff, and/or over only a portion of a wallof the sleeve/cuff, and/or a layer of the sleeve/cuff.

The permeable/semi-permeable region may comprise perforated film, forexample, laser perforated film.

The (e.g. laser) perforated film may be a monolayer film, or a laminateof two or more layers.

The pore size of the (e.g. laser) perforated film may optionally have avariation of less than 20% from an average pore size, optionally lessthan 15% from an average pore size, optionally less than 10% from anaverage pore size, optionally less than 5% from an average pore size.

In some embodiments, the (e.g. laser) perforated film may have athickness of not substantially greater than 0.05 mm. Use of such a thinfilm can contribute to achieving a compact sleeve/cuff for enabling thestent-valve to achieve a desirably small size for delivery bycatheterization. Optionally the film thickness is not substantiallygreater than about 0.045 mm, optionally not substantially greater thanabout 0.04 mm, optionally not substantially greater than about 0.035 mm,optionally not substantially greater than about 0.03 mm, optionally notsubstantially greater than about 0.025 mm, optionally not substantiallygreater than about 0.02 mm, optionally not substantially greater thanabout 0.015 mm, optionally not substantially greater than about 0.01 mm,optionally not substantially greater than about 0.005 mm. In someembodiments, the film thickness may be between about 0.005 mm and about0.015 mm, optionally between about 0.005 mm and about 0.01 mm.

In some embodiments, the (e.g. laser) perforated film may have astrength (e.g. linear tensile strength) at least 50% of the filmstrength prior to laser perforation, optionally at least 60% of thestrength prior to laser perforation, optionally at least 70% of thestrength prior to laser perforation, optionally at least 80% of thestrength prior to laser perforation, optionally at least 90% of thestrength prior to laser perforation. Such characteristics can contributeto a strong film even with thin film thickness.

In some embodiments, the pores (or at least a majority thereof) in the(e.g. laser) perforated film are substantially round and/or have acauterized perimeter and/or have a raised margin around their perimeter.Such a feature or features may contribute individually or in combinationto film strength even with thin film thickness. A round pore shape canavoid sharp corners in the peripheral shape that could be points ofstress concentration or lead to outward crack propagation. Cauterizationof the material around the perimeter of the pore may also advantageouslyreduce risk of outward crack propagation. A raised margin of materialaround the pore perimeter may also provide additional material, andhence strength, surrounding the open area of the pore.

Continuing from the above list, the seal may comprise one or anycombination of two or more of the following features, as well as any ofthe above-noted features, which are all optional:

-   -   The sleeve/cuff may comprise flexible material. The sleeve/cuff        may comprise material that is elastically stretchable, and/or        material that is substantially non-elastically-stretchable.    -   The swellable material may occupy only a portion of the (e.g.        circumferential) length of the sleeve/cuff, for example,        optionally not more than about 75%, optionally not more than        about 60%, optionally not more than about 50%, optionally not        more than about 40%, optionally not more than about 30%,        optionally not more than about 25%, optionally not more than        about 20%.    -   The sleeve/cuff may be transparent or translucent. The swellable        material may have a distinctive color (at least when dry)        enabling the position of the swellable material to be identified        within the sleeve/cuff. Such identification may aid a        practitioner in deciding where optionally to puncture the        sleeve/cuff, if this technique is used, as described later.    -   The sleeve/cuff may have or comprise an integral tubular        structure. As used herein, the term “integral tubular structure”        may mean that the sleeve/cuff or a wall thereof or a layer        thereof, or in the case of a laminate, at least a structural        substrate within the laminate, is produced as an original        integral tube around an axis passing along a centerline of the        tube. As used herein, references to the sleeve/cuff having or        comprising an integral tubular structure apply to at least a        wall, or a layer, or at least a structural substrate of a        laminate, whether or not mentioned explicitly, and whether or        not the entire sleeve/cuff may have such a structure. For        example, integral tubular structures may be made by extrusion of        material in tubular form, or by blow molding a preform to define        a tubular form.

In some embodiments, an integral tubular structure contrasts from a tubethat is non-integrally formed around an axis passing along a centerlineof the tube. Non-integral forming may include, for example, wrapping afilm or sheet around an axis and securing portions to the film or sheetto define a hollow envelope enclosed by the wrapping, or by attachingtwo sheets to define an envelope.

In some embodiments, using an integral tubular structure for thesleeve/cuff may enable the sleeve/cuff to achieve the otherwiseconflicting requirements of desirably thin wall thickness, and goodstrength against bursting. Risk of bursting is often highest atjoin-lines of non-integral structures. Forming an integral tubularstructure reduces the need for extensive join lines, in particular, ajoin line extending circumferentially around the prosthesis (in someembodiments, substantially around).

In some embodiments, in which the stent-valve is configured to beexpanded to an operative configuration by expansion by an inflatableexpansion balloon, providing a stent-valve with a seal sleeve/cuffcomprising an integral tubular structure may be highly advantageous inenabling the seal sleeve/cuff to made desirably thin, yet have goodstrength and resistance to bursting should the seal be subject to theforces applied during the balloon-expansion, especially against theirregular or sharp contours of a calcified native anatomy

Although not immediately intuitive, some embodiments of the presentdisclosure provide a technique of post-implantation balloon-expansion ofan implanted prosthesis stent-valve carrying a swellable seal. Providinga stent-valve with a seal sleeve/cuff comprising an integral tubularstructure may be highly advantageous in enabling the seal sleeve/cuff tomade desirably thin, yet include strength and resistance to burstingshould the seal be subject to the high forces applied duringpost-implantation balloon-expansion, especially against the irregular orsharp contours of a calcified native anatomy. For example, such forcesmay be greater than normally experienced by the seal during initialimplantation (whether by self-expansion of the stent-valve, or by manualmanipulation, for example, initial balloon expansion). Additionally oralternatively, it may permit a second implantation procedure (forexample, even many years into the future), which may itself involve avalvuloplasty procedure using an expansion balloon to prepare forimplantation of a further prosthesis. The fact that the currentstent-valve comprises a seal configured to withstand balloon expansion(e.g. valvuloplasty) forces without risk of bursting, may continue toprovide the patient with the full range of options for future treatment(which might not be available to a patient who has been implanted with adifferent type of swelling seal not designed to withstand a futureballoon expansion and/or valvuloplasty procedure).

Continuing from the list above, the seal may comprise one or anycombination of two or more of the following features, as well as any ofthe above-noted features, which are all optional.

-   -   Whether or not the sleeve/cuff is formed as or comprising an        integral tubular structure, the sleeve/cuff may comprise a        tubular extrusion or blow molded tubing.    -   In addition to, or as an alternative to, the above, the        sleeve/cuff may be configured to be able to withstand        post-implantation balloon expansion of the stent-valve against a        calcified anatomy without substantial loss of structural        integrity of the hollow sleeve/cuff. This can provide similar        advantages for permitting balloon expansion (e.g.        post-implantation balloon expansion) and/or suitability for a        future valvuloplasty procedure.    -   The hollow sleeve/cuff may be formed from or using a tubular        segment from an inflatable cardiac valvuloplasty balloon. Such        balloon material already has desirable characteristics of being        thin-walled yet strong to resist bursting when the balloon is        inflated and bears directly against hard, irregular and sharp        calcifications of a calcified vascular anatomy. The balloon        material is also established as being bio-compatible and        suitable for introduction into, and for direct contact with, the        human vasculature. Optionally, the material may be        laser-perforated, depending on whether it is desired to provide        a permeable (or at least semi-permeable) characteristic.    -   The sleeve/cuff may be formed by a method including providing an        elongate hollow tubular member (optionally with an integral        tubular structure), introducing the swellable material into the        interior of the tubular member, and optionally bending the        elongate tubular member to form a substantially toroid shape        (e.g. when mounted on the prosthesis).    -   The opposite ends of the (e.g. bent) elongate tubular member may        be secured together (for example, by fusion, welding, or        adhesive) to define a closed-loop toroid form, whether or not        the ends of the tube communicate openly with each other as a        continuous open interior space. Alternatively, the opposite ends        of the (e.g. bent) elongate tubular member may remain        disconnected from each other, even after mounting on the        prosthesis.    -   The hollow sleeve/cuff, or at least a layer or wall thereof, may        be liquid-tight, at least prior to use of the prosthesis.    -   The hollow sleeve/cuff, or at least a layer or wall thereof, may        comprise polymeric material and further comprise a diffusion        barrier layer to obstruct diffusion of liquid through the        sleeve/cuff wall and into the space containing the swellable        material.    -   The hollow sleeve/cuff, or at least a layer or wall thereof, may        comprise a laminate of (1) plastics film and (2) a diffusion        barrier layer to obstruct diffusion of liquids from outside the        hollow sleeve/cuff to the hollow interior. The diffusion barrier        optionally is formed either on an interior face of the        sleeve/cuff or a layer or wall thereof (e.g. the hollow interior        face), or as a non-surface layer of the laminate. Such        positioning of the diffusion barrier layer may protect the        integrity of the diffusion barrier layer during production and        assembly of the prosthesis, enabling easier handling.    -   The diffusion barrier material of either of the above may be of        or comprise a metal or metal compound (e.g., an oxide).    -   The metal or metal compound may be formed by plasma vapour        deposition. The thickness of the layer may be optionally less        than 100 nm, optionally less than 50 nm, optionally less than 10        nm.    -   The diffusion barrier layer may be configured to remain in        position on the prosthesis when the prosthesis is implanted.    -   Additionally or alternatively, at least a portion of the        sleeve/cuff (or at least a portion of a layer or wall thereof)        may be configured to be removable to define an area through        which liquid (e.g. blood) may be admitted, in use, for causing        the swellable material to swell. The removable portion may, for        example, be a portion of the or a liquid-tight layer or wall.    -   Additionally or alternatively, the sleeve/cuff material is        configured to be pierced in use, prior to introduction into the        body of a patient, to create liquid-admitting punctures in the        sleeve/cuff material.    -   The prosthesis may be provided as part of a kit including a        piercing tool usable to pierce the sleeve/cuff to form        liquid-admitting punctures in the cuff. The piercing tool may        comprise at least one pin or other sharp projection. The (or        each) pin or protection may be dimensioned to permit puncturing        of the sleeve/cuff without damaging other operative portions of        the prosthesis (for example, without damaging leaflets of a        stent-valve). The piercing tool may, for example, comprise a        roller carrying the at least one (and preferably plural) pin or        other sharp projection. The roller may be configured to be        rollable over a region of the cuff/sleeve to effect the piercing        action.    -   In some embodiments, the sleeve/cuff may be pierced before,        during, or after, loading of the prosthesis (e.g. stent-valve)        into a delivery catheter. In some examples, the delivery        catheter includes a sheath within which the prosthesis (e.g.        stent-valve) is at least partly contained when loaded (or during        loading). The sheath may include at least one (and optionally a        plurality) of apertures aligned with the sleeve/cuff, and        through which the piercing tool may be introduced to pierce the        sleeve/cuff while in situ in the delivery catheter.    -   In one example condition of a stent-valve prior to introduction        of the stent-valve into the body of a patient, the stent-valve        has a seal sleeve/cuff containing a swellable material. The        sleeve/cuff is liquid impermeable except for at least one (and        optionally a plurality) of liquid-admitting punctures made        therein, for admitting liquid into the seal. Additionally or        alternatively, the sleeve/cuff is made of liquid-impermeable        material, the sleeve/cuff having one or more liquid admitting        punctures made therein for admitting liquid into the seal.    -   In one example condition of a stent-valve prior to introduction        of the stent-valve into the body of a patient, the stent-valve        according to some embodiments includes a seal sleeve/cuff        containing a swellable material. The swellable material is at        least partly hydrated or wetted by liquid (e.g., prior to        introduction of the stent-valve into the body). The sleeve/cuff        may be constrained against substantial expansion by being        constrained within a sheath of a delivery apparatus. The        hydrating or wetting liquid may, for example, be saline.        Allowing the seal sleeve/cuff to at least partly hydrate or        become at least party wetted prior to introduction into the body        may enable more efficient swelling of the material, and        therefore of the sleeve/cuff, when the stent-valve is implanted.        It can avoid the need for the seal to have to become wetted by        liquid only on implantation. For example, speed of wetting        and/or swelling may be a consideration if the liquid-admitting        apertures (e.g. punctures) in the sleeve/cuff are relatively        small and/or if a relatively “slow” hydrating/swelling material        is used within the sleeve/cuff.    -   Additionally or alternatively to the above, in one example        condition of a stent-valve prior to introduction of the        stent-valve into the body of a patient, the stent-valve is        loaded at least partly into a delivery catheter. The delivery        catheter comprises a containment sheath encompassing at least a        portion of the stent-valve at which the seal is located, the        containment sheath being at least partly filled with liquid, and        the swellable material being exposed to the liquid, the        containment sheath obstructing expansion of the seal. The liquid        may, for example, be saline.    -   The seal may further comprise a skirt secured to the hollow        sleeve/cuff, for example, using an attachment that does not        puncture the cuff Example attachments may include one or more        of: fusion; welding, adhesive. The skirt may itself be attached        to the stent, for example, by sutures. The skirt may provide a        means by which the seal is fixed to the stent. Such a technique        can enable the seal to be secured fixed to the stent, without        risk that the stent fixings may compromise the integrity of the        cuff.    -   The stent-valve (optionally all of the stent, valve-leaflets,        and seal) may be compressible to a compressed configuration for        delivery, and expandable to an operative configuration at        implantation. In some embodiments, the stent is a self-expanding        type that self-expands at least partly towards (and preferably        self-expands entirely to) the operative configuration.        Additionally or alternatively, the stent may be manually        manipulable (e.g. plastically expandable) to the operative        configuration, for example, using an expansion balloon or other        expanding device or foreshortening device. The material of the        stent, in either case, may for example be selected from one or        more of: shape memory material; shape memory metal alloy;        nitinol; steel, nickel-chromium (containing) alloy;        chromium-cobalt (containing) alloy.    -   As mentioned previously above, the seal may be provided as a        separate item from the prosthesis (e.g. stent-valve), and be        mountable to the stent-valve, for example, as part of a        pre-implantation preparation process.    -   Various techniques are envisaged for mounting a separate seal to        the prosthesis.    -   One mounting technique may be using adhesive, for example, an        adhesive surface that is provided on the prosthesis and/or the        seal. The adhesive surface may initially be protected by a        release sheet or strip that is removable (e.g. peelable) from        the adhesive surface, to expose the adhesive surface ready for        attaching the seal to the prosthesis.    -   Additionally or alternatively, the prosthesis may comprise a        dedicated seal accommodation region to which the seal is        mountable.    -   The seal accommodation region may comprise an adhesive surface        or a landing surface for adhesive engagement as aforementioned.    -   Alternatively, the seal accommodation region may comprise a        substantially continuous, or a discontinuous, accommodation        channel for receiving at least a portion of the seal. A        discontinuous channel may be formed, for example, by a series of        spaced apart loops similar to clothing belt loops. Each loop may        be relatively short in circumferential extent and/or the number        of loops may be relatively small, to define a relatively small        mark/space ratio (e.g. closed-area/open-area ratio) of less than        1, optionally less than about 0.75, optionally less than about        0.5, optionally less than about 0.25. Alternatively, each loop        may have a circumferential length such that, and/or the number        of loops may be relatively high such that, the ratio is at least        about 1, optionally at least about 1.25, optionally at least        about 1.5, optionally at least about 1.75, optionally at least        about 2, optionally at least about 2.5, optionally at least        about 3. A substantially continuous channel may be formed, for        example, by one of more of: a tubular structure; a        circumferential flap; an open sided channel; a circumferential        envelope or pocket.    -   A loading filament (e.g. of suture wire), may be pre-laid within        the accommodation channel to facilitate loading of the seal into        the channel. For example, one end of the loading filament may be        attachable to the seal (for example, to one end of an elongate        seal). Pulling on the opposite end of the loading filament may        draw the seal into the channel.    -   The accommodation channel may include one or a plurality of        openings and/or clearances for admitting blood to the seal. At        least some of the openings and/or clearances may, for example,        be arranged: (i) facing substantially or at least partly towards        the prosthesis blood outlet end; and/or (ii) facing        substantially or at least partly towards the prosthesis blood        inlet end; and/or facing substantially in a generally radial        inward and/or radial outward direction. The openings and/or        clearances, however arranged, may optionally be permanently open        such that the openings and/or clearances do not substantially        prevent entry of liquid to the accommodation channel. The        openings and/or clearances, however arranged, may have a size        that does not substantially obstruct communication therethrough.    -   The accommodation region (e.g. accommodation channel) may        optionally form part of or be coupled to an outer skirt fitting        on an exterior surface of the prosthesis. The skirt may        optionally comprise film, or fabric, or a combination of film        and fabric.    -   The outer skirt may optionally be permanently attached to an        inner skirt positioned within the prosthesis. The permanent        attachment may be provided by, for example, welding, adhesive or        suturing. The inner and outer skirts may be attached together        along at least one line (or intermittent line) that is generally        continuous at least in a circumferential direction around the        prosthesis. Such a line of attachment can enhance the prevention        of leak paths for blood that could otherwise exist between the        inner and outer skirts were the skirts not so attached.

Further embodiments of the disclosure may relate to a method ofproduction of a prosthesis (e.g. a stent-valve), optionally as definedby any one or any combination of two or more of the foregoing aspectsand features. The method may comprise one or any combination of two ormore of the following steps and/or features, which are all optional.

-   -   A seal of, or for, the prosthesis may be provided comprising a        sleeve/cuff containing a swellable material. The sleeve/cuff may        optionally be a sealed liquid tight sleeve/cuff, and/or the        sleeve/cuff may be provided within a sealed liquid-tight        container.    -   The seal may be attached to the prosthesis as an integral part        of the prosthesis, or the seal may be provided as a separate        component that is attachable to the prosthesis (for example, as        part of a pre-implantation preparation process), or the seal may        comprise at least one component that is introducible to (e.g.        injectable into) a respective region of the prosthesis (for        example, as part of a pre-implantation preparation process).    -   During the method of production, after assembling the components        of the prosthesis (e.g. a stent, one or more prosthetic valve        leaflets, and optionally the seal if provided in integrally        attached form), the stent-valve may be immersed into a liquid.        For example, the liquid may be a sterilizing liquid and/or a        preservative liquid for packaging the stent-valve ready for use.    -   The liquid-tight sealed sleeve/cuff may prevent the liquid from        contaminating the swellable material of the seal prior to        intended use.    -   The liquid may be toxic to the human blood stream (for example,        intended to be rinsed or otherwise cleaned off the prosthesis        (e.g. stent-valve) before the prosthesis is introduced into a        patient's body).    -   A tubular sleeve/cuff of the seal (and/or a wall and/or a layer        and/or a structural substrate of a laminate thereof) may be        formed by an integral tubular forming technique. Example        techniques may include tubular extrusion and/or blow molding.    -   A tubular sleeve/cuff of the seal (and/or a wall and/or a layer        and/or a structural substrate of a laminate thereof) may be        obtained from a segment of a valvuloplasty balloon.    -   A tubular sleeve/cuff may be provided by the steps including        providing an elongate hollow tubular member (optionally with an        integral tubular structure), introducing the swellable material        into the interior of the tubular member. Optionally the steps        further include bending the elongate tubular member to form a        substantially toroid shape.    -   The opposite ends of the (e.g. bent) elongate tubular member may        be closed (for example, by fusion, welding or adhesive).        Additionally or alternatively, the opposite ends of the (e.g.        bent) elongate tubular member may be secured together (for        example, by fusion, welding, or adhesive) to define a        closed-loop toroid form. The opposite ends may be sealed closed        to define a non-continuous interior of the sleeve/cuff at the        join in the toroid, or they may communicate with each other to        define a continuous open interior across the join.    -   A diffusion barrier layer may be formed on a tubular sleeve/cuff        of the seal, or on a material blank used to form the tubular        sleeve/cuff, and/or on other cover material for a seal        comprising swellable material.    -   The diffusion barrier layer may be or comprise a metal or metal        compound.    -   The diffusion barrier layer may be formed by plasma vapour        deposition.    -   The method may include sterilizing the seal, and/or sterilizing        a component used to form the liquid-tight sealed sleeve/cuff        containing swellable material, by irradiation.    -   The method may include sterilizing the prosthesis (e.g.        stent-valve), after assembly, by contacting the prosthesis with        a sterilizing fluid, e.g. immersing the stent-valve in a        sterilization liquid. If provided, the liquid-tight sealed        sleeve/cuff may prevent liquid contamination of the swellable        material. The sterilization liquid may optionally comprise an        aldehyde, optionally glutaraldehyde.    -   The method may include storing the prosthesis (e.g.        stent-valve), ready for use, in liquid preservative. If        provided, the liquid-tight sealed sleeve/cuff may prevent liquid        contamination of the swellable material. The liquid preservative        may optionally comprise an aldehyde, optionally glutaraldehyde.    -   The method may include sterilizing a sealed sleeve/cuff, and        sterilizing swellable material therein, using a different        sterilizing technique from the remainder the prosthesis (e.g.        stent valve). For example, the sleeve/cuff, and the swellable        material may be sterilized using radiation. The remainder of the        prosthesis (e.g. stent-valve) may be sterilized by contacting        the prosthesis with a sterilizing liquid (or other sterilizing        fluid).    -   In addition to or alternatively to any of the foregoing, a        method of producing a prosthesis or a seal for or of a        prosthesis, may comprise providing a wall or layer of material,        the material including at least a laser-perforated region. The        wall or layer of material may be provided as, or be formed into,        a sleeve/cuff of a seal for containing a swellable material that        swells when contacted by blood. The laser-perforated region may        extend over substantially the entire area of the material, or at        least a majority of the material, or over only a selected zone        leaving a further zone without any perforations.    -   In addition to or alternatively to any of the foregoing, a        method of producing a prosthesis or a seal for or of a        prosthesis, may comprise the step of laser perforating a region        of material. The material may be in the form of, or subsequently        formed into, a sleeve/cuff of a seal for containing swellable        material that swells when contacted by blood. The step of laser        perforating may comprise perforating substantially the entire        area of the material, or at least a majority of the material, or        only a selected zone leaving a further zone without any        perforations.

Further embodiments of the present disclosure may relate to a method ofpreparing and/or using a prosthesis (e.g. stent-valve) for implantation,the prosthesis optionally as defined and/or produced by any one or anycombination of two or more of the foregoing aspects and features. Themethod of using and/or preparing may comprise one or any combination oftwo or more of the following steps and/or features, which are alloptional:

-   -   providing (i) the prosthesis (e.g. stent-valve) stored in a        storage solution, and (ii) a seal comprising a material that        swells when contacted. Optionally the seal is included as part        of the prosthesis. Alternatively, at least a component of the        seal is provided as a separate item from the prosthesis, and is        mountable to, and/or introducible to, and/or injectable into the        prosthesis as part of the method. For example, the seal or seal        component may be provided as a separate component mountable to        the prosthesis, or alternatively as a flowable component that is        injectable into a seal part of the prosthesis.    -   The seal may comprise a material that swells when contacted by        liquid and a sleeve/cuff or cover. The sleeve/cuff and/or cover        may protect the seal from contact by the storage solution, if        the seal is provided as part of the prosthesis within the        storage solution.    -   rinsing the stent-valve to clean the stent-valve of the storage        solution;    -   after rinsing, piercing the sleeve/cuff or cover at one or more        positions to break the integrity of the sleeve/cuff or cover, in        order to allow blood to contact the swellable material upon        implantation;    -   after rinsing, mounting the seal to the prosthesis (if the seal        is provided as a separate component).    -   additionally or alternatively, after rinsing, compressing and/or        loading the stent-valve into a delivery apparatus for        introduction into the body;    -   additionally or alternatively, after rinsing and while the        stent-valve is outside a human body, exposing the swellable        material to, and/or contacting the swellable material with,        liquid to allow at least partial wetting or hydration of the        swellable material; and    -   the step of exposing may be carried out before, or during, or        after the step of compressing. For example, the liquid may be        liquid within which the stent-valve is at least partly        immersed (i) during compressing and/or loading, or (ii) within        the delivery catheter.

In a closely related aspect, the invention relates to a further methodof using a stent-valve for implantation, the stent-valve optionally asdefined and/or produced by any one or any combination of two or more ofthe foregoing aspects and features. The method of using may comprise oneor any combination of two or more of the following steps and/orfeatures, which are all optional:

-   -   providing a stent-valve that is compressible to a compressed        configuration for delivery, and expandable to an operative        configuration for implantation, the stent-valve comprising a        stent, a plurality of leaflets defining a prosthetic valve, and        a seal for sealing against surrounding tissue, the seal        comprising a swellable material that swells when contacted by        blood (and the seal being optionally a part of the prosthesis,        or at least a component of the seal being a separate component        that is mounted to or injected into the prosthesis as part of        the method);    -   introducing the stent-valve into the body in its compressed        configuration using a delivery device, and advancing the        stent-valve to a desired implantation site;    -   causing the stent-valve to expand at the implantation site, from        the compressed configuration to its operative configuration;    -   observing one or more characteristics of the operative        stent-valve; and    -   in dependence on the result of the observation at step (d),        performing post-implantation balloon expansion of the        stent-valve.

Features and advantages of some of the embodiments of the disclosure,include:

-   -   facilitating a seal construction that is able to swell to        automatically seal gaps between the stent-valve and the        surrounding tissue, even in the case of an irregular anatomy;    -   facilitating safe post-dilation of the stent-valve as desired,        without significant risk of seal rupture;    -   facilitating long storage times of a stent-valve without risk of        contaminating the swellable material of the seal by toxic        storage solution;    -   facilitating thorough sterilization of a stent-valve without        contaminating or otherwise compromising the swellable material        of a seal;    -   facilitating simple yet effective activation of the swellable        material of a seal without having to separate components;    -   facilitating early partial hydration or wetting of a swellable        seal before implantation, to reduce the burden of seal to access        liquid only at the instant of deployment at the implantation        site;    -   avoiding the need for any rupture of a capsule membrane during        the implantation process, by facilitating exposure of a        swellable seal material to liquid prior to introduction into the        body, and carrying out such exposure while the seal is        constrained against expansion.

Additional and/or independent embodiments and features of the disclosureare included in the claims.

Although certain features and aspects of the invention are highlightedin the foregoing summary and in the appended claims, protection isclaimed for any novel concept described herein and/or illustrated in thedrawings, whether or not emphasis is placed thereon.

BRIEF DESCRIPTIONS OF THE OF THE DRAWINGS

Non-limiting embodiments of the invention are now described withreference to the accompanying drawings, in which:

FIG. 1 is a schematic drawing illustrating a stent-valve 10 with whichsome embodiments of the present disclosure are suitable to be used. Thefigure is broken along a centre-line of the stent-valve. Thestent-structure is shown to the right, and a profile showing thepositions of the valve, skirt and seal is shown to the left.

FIG. 2 is an enlarged schematic section showing the seal of FIG. 1 inisolation.

FIG. 3 a is a schematic perspective view of an elongate tubular memberfor use in the production of a seal according to some embodiments of thedisclosure.

FIG. 3 b is a schematic section illustrating obtaining the tubularmember from a valvuloplasty balloon according to some embodiments of thedisclosure.

FIG. 3 c is a schematic partial perspective view of a sub-assemblyincluding tubing and outer skirt material according to some embodimentsof the disclosure.

FIG. 3 d is a schematic section illustrating an example of forming thesub-assembly of FIG. 3 c, according to some embodiments of thedisclosure.

FIG. 3 e is a schematic view illustrating insertion of swellablematerial into the sub-assembly of FIG. 3 c.

FIG. 3 f is a schematic side view illustrating assembly of thesub-assembly to the stent of FIG. 1.

FIG. 3 g is a schematic side view illustrating formation of a conicaltubular sub-assembly for assembly to the stent of FIG. 1.

FIG. 4 is a schematic section illustrating a seal sleeve/cuff providedwith a diffusion barrier layer according to some embodiments of thedisclosure.

FIG. 5 is a schematic flow diagram illustrating steps of a method forproducing a stent-valve according to some embodiments of the disclosure.

FIG. 6 is a schematic flow diagram illustrating steps of a method ofpreparing a stent-valve for implantation according to some embodimentsof the disclosure.

FIG. 7 is a schematic side view of a piercing tool for piercing a sealsleeve/cuff of a stent-valve according to some embodiments of thedisclosure.

FIG. 8 is a schematic section of a first example of delivery cathetercontaining a stent-valve loaded therein according to some embodiments ofthe disclosure.

FIG. 9 is a schematic section of a second example of delivery cathetercontaining a stent-valve loaded therein according to some embodiments ofthe disclosure.

FIG. 10 is a schematic flow diagram illustrating steps of a method ofimplanting a stent-valve according to some embodiments of thedisclosure.

FIG. 11 is a schematic section of a first example of a seal according tosome embodiments of the disclosure.

FIG. 12 is a schematic section of a second example of a seal accordingto some embodiments of the disclosure.

FIG. 13 is a schematic view of a first example of a perforated filmaccording to some embodiments of the disclosure.

FIG. 14 is a schematic view of a second example of a perforated filmaccording to some embodiments of the disclosure.

FIG. 15 is a schematic section illustrating a seal sleeve/cuff providedwith an impermeable layer according to some embodiments of thedisclosure.

FIG. 16 is a schematic drawing illustrating a stent-valve 10 with whichsome embodiments of the present disclosure are suitable to be used. Thefigure is broken along a centre-line of the stent-valve. Thestent-structure is shown to the right, and a profile showing thepositions of exemplary valve and seal accommodation regions is shown tothe left. The figure also depicts an exemplary separately-provided seal.

FIG. 17 is a schematic drawing illustrating an exemplary sealaccommodation region, as part of an outer skirt, including spaced apartloops, according to some embodiments of the disclosure.

FIG. 18 is a schematic drawing illustrating an exemplary sealaccommodation channel, as part of an outer skirt, including a flap,according to some embodiments of the disclosure.

FIG. 19 is a schematic drawing illustrating an exemplary sealaccommodation channel, as part of an outer skirt, including a flapcomprising castellated extensions, according to some embodiments of thedisclosure.

FIG. 20 is a schematic drawing illustrating an exemplary sealaccommodation channel, as part of an outer skirt, including a flapcomprising a scalloped edge, according to some embodiments of thedisclosure.

FIG. 21 is a schematic drawing illustrating an exemplary sealaccommodation channel, as part of an outer skirt and comprising a tube(or an envelope), according to some embodiments of the disclosure.

FIG. 22 is a schematic drawing illustrating a stent-valve 10 with whichsome embodiments of the present disclosure are suitable to be used. Thefigure is broken along a centre-line of the stent-valve. Thestent-structure is shown to the right, and a profile showing thepositions of exemplary valve and seal accommodation regions is shown tothe left. The figure also depicts an exemplary separately-provided sealbearing an adhesive region.

FIG. 23 is a schematic section showing an exemplary seal, according tosome embodiments of the disclosure. The figure also depicts an exemplaryintroduction of a flowable swellable material through an optional inletport of the seal.

FIG. 24 is a schematic drawing illustrating an exemplary outer skirt,according to some embodiments of the disclosure, comprising attachmentzones on either side of a seal accommodation region.

FIG. 25 is a schematic section showing an exemplary outer skirtcomprising a sheet of film material, according to some embodiments ofthe disclosure.

FIG. 26 is a schematic section showing a first example of an outer skirtcomprising a sheet of film material and fabric material, according tosome embodiments of the disclosure.

FIG. 27 is a schematic section showing a second example of an outerskirt comprising a sheet of film material and fabric material, accordingto some embodiments of the disclosure.

FIG. 28 is a schematic section showing a third example of an outer skirtcomprising a sheet of film material and fabric material, according tosome embodiments of the disclosure.

FIG. 29 is a schematic drawing illustrating a stent-valve 10 with whichsome embodiments of the present disclosure are suitable to be used. Thefigure is broken along a centre-line of the stent-valve. Thestent-structure is shown to the right, and a profile showing thepositions of exemplary valve and seal accommodation regions is shown tothe left. The figure also depicts an exemplary separately-provided sealthat is correspondingly broken along its centre-line, depicting asaddle/harness for attachment to the stent.

FIG. 30 is a schematic flow diagram illustrating steps of a method ofusing and/or preparing a stent-valve for implantation according to someembodiments of the disclosure.

Referring to FIG. 1, a stented prosthesis according to some embodimentsis illustrated in the form of a stent-valve 10. A seal 40 (describedfurther below) may be provided for sealing against surrounding tissuewhen the stent-valve 10 is implanted. The stent-valve 10 may be cardiacstent-valve, for example, an aortic stent-valve, a mitral stent-valve, apulmonary stent-valve or a tricuspid stent-valve, for implantation atthe respective valve position in a human heart.

The stent-valve 10 may optionally comprise biological tissue (forexample, pericardium (such as porcine pericardium and/or bovinepericardium) and/or natural cardiac valve leaflets (for example, naturalporcine cardiac valve leaflets, optionally attached to a portion ofnatural cardiac wall tissue). The biological tissue may be fixed, forexample, using glutaraldehyde.

The stent-valve 10 may be compressible to a radially compressedcondition (FIG. 8) for delivery using a delivery catheter, and beexpandable to an operative or expanded condition (as shown) atimplantation. The stent-valve 10 may comprise a stent 12 carrying aplurality of leaflets defining a valve 14 (the position of which isdepicted schematically by the bounding phantom lines). Variousgeometries of stent 12 may be used. In some embodiments, the stent 10may include one of more of: a lower tubular or crown portion 16, anupper crown portion 18, a plurality of upstanding commissural supports20, and a plurality of stabilization arches 22. In use, the lowerportion 16 of the stent 12 may be configured to be deployed after theother regions of the stent 12. For example, the arches 22, the supports20 and the upper crown 18 may be deployed at least partly before thelower portion 16 (in that order, or in reverse order, or in a differentorder). At the very least, once the upper crown 18 has been at leastpartly deployed, the stent 12 may be urged and/or displaced in thedirection of arrow 24 to seat the upper crown 18 against native leafletsat the implantation site. Deploying the lower portion 16 last fixes thestent 12 in its final position.

The lower portion 16, and optionally a portion of the upper crown 18,may be formed by a lattice structure of the stent. The lattice structuremay define cells or apertures, for example, generally diamond-shapedapertures.

The native leaflets may generally overlap a portion 26 of the stent. Thenative valve annulus may overlap a portion 28 of the stent.

Optionally, the stent-valve 10 may further include an inner skirt 30communicating with the leaflets 14 and carried on an interior of thestent 12. Additionally or alternatively, the stent-valve 10 may furthercomprise an outer skirt 32 carried on an exterior of the stent 12. Whenboth skirts are provided, the skirts may partially overlap. The skirtsmay be offset such that one skirt (e.g. the outer skirt 32) extendsfurther towards a lower extremity of the stent 12 than the other (e.g.inner skirt 30). Additionally or alternatively, one skirt (e.g. theinner skirt 30) extends further towards an upper extremity of the stent12 than the other (e.g. outer skirt 32). The skirts may be of anysuitable flexible and/or compliant material, for example, fabric (e.g.of PET) or of biological tissue (e.g. of pericardium).

Optionally, the inner skirt 30 and the outer skirt 32 may be attacheddirectly to each other along at least one substantially continuous ordiscontinuous line of attachment. The attachment may, for example, be byone of more of: suturing, welding, fusion, adhesive. The line ofattachment may optionally extend around the entire circumference of thestent-valve. The attachment may mitigate risk of leakage of blood in thespaces of the stent between the inner and outer skirts 30 and 32.

Optionally, at least the outer skirt 32 is positioned to leave the uppercrown 18 substantially unobscured by the outer skirt 32. Such anarrangement may assist good blood flow to the coronary arteries (forexample, in the case of a stent-valve for the aortic valve).

In some embodiments, the lower portion 16 has an extremity formed with asubstantially zig-zag shape. The zig-zag shape may comprise lower apexes16 a and upper apexes 16 b. The upper apexes 16 b may be masked in FIG.1 by the superimposed presentation of both the frontmost and rearmostcells of the lattice structure. The zig-zag shape may be substantiallycontinuous around the circumference of the stent 12. The outer skirt 32may have a peripheral edge having a zig-zag shape that matchessubstantially the zig-zag shape of the extremity of the lower portion16. Such an arrangement can avoid excessive material at the extremity,and thereby facilitate crimping of the stent-valve 10. At the same time,the outer skirt 32 covers (for example, complete) open cells of thelattice structure down to the stent extremity to reduce risk of bloodleakage through the apertures of the cells. The outer skirt 32 can alsoprovide a layer of material over the struts of the stent, thereby tocushion the engagement between the stent and the sensitive native hearttissue.

The valve 14 may comprise biological tissue, for example, pericardium(such as porcine pericardium or bovine pericardium) or natural cardiacvalve leaflets (for example, natural porcine cardiac valve leaflets,optionally attached to a portion of natural cardiac wall tissue). Otherbiological or non-biological material could also be used for the valve14, as desired.

The stent 12 may optionally be of a self-expanding type that iscompressible to the compressed configuration for loading into a deliverycatheter 98 (FIG. 8) having a sheath 106 for constraining the stent 12in the compressed configuration for delivery to the site ofimplantation. In use, by removal of the constraining effect of thesheath, the stent 12 self-expands to or towards the operativeconfiguration. A self-expanding stent may, for example, be ofshape-memory material, for example, shape-memory metal alloy, forexample, nitinol. Alternatively, the stent 12 may be configured to beexpanded by application of a foreshortening force from the deliverycatheter and/or by application of expanding force from the deliverycatheter, such as by using an expansion balloon.

The seal 40 may be configured for sealing against surrounding nativetissue when the stent-valve 10 is implanted. In some embodiments, theseal 40 may be provided as an integral part of the stent-valve 10.Alternatively, in some embodiments, at least a component of the seal 40may be provided as a separate item from the stent-valve. The at leastone component may, for example, be mountable to the stent-valve 10 priorto implantation, or it may be introduced (e.g. injected) into a portionof the stent-valve. The at least one component may be mounted/introducedas part of a pre-implantation preparation process (for example,described later).

The seal 40 may be arranged or arrangeable at any suitable position onthe stent 12. In some embodiments, the seal 40 may be arranged betweenthe upper crown portion 18 and the lower crown or tubular portion 16. Insome embodiments, the seal 40 may be positioned optionally closer to theupper crown portion 18, alternatively optionally closer to the lowercrown or tubular portion 16, alternatively optionally midway between theextremities of the two crown portions 16 and 18, alternativelyoptionally at a waist or trunk section between the two crown portions 16and 18. In some embodiments, the seal 40 is carried on the exterior ofthe stent 12.

As mentioned above, in some embodiments, the (e.g. lower or inlet)periphery of the stent 12 has a substantially zig-zag shape. The zig-zagshape may comprise lower apexes 16 a and upper apexes 16 b. The upperapexes may be masked in FIG. 1 by the superimposed presentation of boththe frontmost and rearmost cells of the lattice structure. The zig-zagshape may be substantially continuous around the circumference of thestent 12. The seal 40 may be arranged or arrangeable to be positionedonly between the upper crown 18 and the upper apexes 16 b. For example,the seal 40 does not extend to occupy space between the upper apexes 16b and the lower apexes 16 a. Positioning the seal 40 clear of the lowerapexes 16 a can reduce the bulk of material at the extremity, andfacilitate crimping. Additionally or alternatively, the seal may bepositioned so as not to cover the upper crown 18. Leaving the uppercrown 18 clear may enhance blood flow to coronary arteries (for example,in the case of a replacement valve for the aortic valve position).

Referring to FIG. 2, the seal 40 may comprise a hollow sleeve/cuff 42arranged to extend substantially in a circumferential direction aroundthe stent 12, and containing swellable material 44 that swells whencontacted by blood to distend the hollow sleeve/cuff 42. The swellablematerial 44 may expand by absorbing blood or other liquids that contactthe material 44. Such a seal 40 may initially be very compact in form,yet may expand significantly when contacted by blood, to fill gapsbetween the stent-valve 10 and any irregularities in the surroundingtissue. Examples of suitable swellable (e.g. absorptive) material 44 maybe any of the hydrogels referred to in the aforementioned patents andapplications: U.S. Pat. No. 5,769,882, EP 1262201, WO-A-2008/070442, US2007/0060998, WO-A-2010/083558. The sleeve/cuff 42 may comprise flexiblematerial. The sleeve/cuff 42 may comprise material that is elasticallystretchable, and/or material that is substantiallynon-elastically-stretching.

In some embodiments, the hollow sleeve/cuff 42 or a wall or layerthereof, has or comprises an integral tubular structure. An integraltubular structure may mean that the sleeve/cuff (or wall or layer) 42 isproduced as or comprises an original integral tube around an axispassing along a centerline of the tube; in the case of the sleeve/cuff42 having or comprising a laminate structure, at least a structuralsubstrate (e.g. substrate layer) within the laminate may be produced asan integral tube around an axis passing along a centerline of the tube.As used herein, references to the sleeve/cuff 42 having or comprising anintegral tubular structure also apply to at least a wall or layer or astructural substrate of the laminate, whether or not mentionedexplicitly, and whether or not the entire sleeve/cuff 42 may have such astructure. For example, integral tubular structures may be made byextrusion of the sleeve/cuff 42 material in tubular form, or by blowmolding a preform to define a tubular form. Using an integral structurefor the sleeve/cuff 42 may enable the sleeve/cuff 42 to achieve theotherwise conflicting requirements of desirably thin wall thickness, andgood strength against bursting. Risk of bursting is often highest atjoin-lines of non-integral structures. Forming an integral tubularstructure reduces the need for extensive join lines, in particular, ajoin line extending circumferentially around (and in some embodiments,substantially around) the prosthesis.

As illustrated later below, in some embodiments, an implantation methodmay include a step of (e.g., post-implantation) balloon-expansion of animplanted prosthesis stent-valve 10 carrying a seal 40. Providing thestent-valve 10 with a seal sleeve/cuff 42 having or comprising anintegral tubular structure may be highly advantageous in enabling theseal sleeve/cuff 42 to made desirably thin, yet have good strength andresistance to bursting should the seal be subject to the high forcesapplied during (e.g. post-implantation) balloon-expansion, especiallyagainst the irregular or sharp contours of a calcified native anatomy.

Referring to FIG. 3, whether or not of an integral tubular structure,the material for the sleeve/cuff 42 may initially be provided inelongate tubular form 46 (FIG. 3 a), for example, as an elongateintegral tube. In some embodiments, (whether or not of an integraltubular structure) such an elongate tube 46 may be obtained from aballoon section of an inflatable cardiac valvuloplasty balloon 48 (FIG.3 b), for example, by cutting the balloon 46 a near its ends, to extractan elongate tubular segment as the tube 46. Such balloon materialalready has desirable characteristics of being thin-walled yet strong toresist bursting when the balloon is inflated and bears directly againsthard, irregular and sharp calcifications of a calcified vascularanatomy. The balloon material is also established as beingbio-compatible and suitable for introduction into, and for directcontact with, the human vasculature.

Whether or not obtained from a cardiac valvuloplasty balloon, andwhether or not having an integral tubular structure, example materialsfor the sleeve/cuff 42, or tube 46, may include one or more of:polyamide (PA), polyimide (PI), polyetheretherketone (PEEK), polyester(PE), for example, polyethylene terephthalate (PET).

Referring to FIG. 3 c, in some embodiments using a seal 40 that isintegral with the stent-valve 10, the elongate tube 46 may be attachedto material 48, such as a material blank, for forming the outer skirt32. The attachment of the tube 46 to the blank 48 is preferably by anattachment that does not puncture the elongate tube 46 for thesleeve/cuff 42. The tubular integrity of the tube 46 may be preserved.The attachment may, for example, be by fusion, or welding, or adhesive.In some embodiments, the blank 48 may be of the same material as thetube 46, to facilitate attachment, for example, by fusion. Creation of asub-assembly 50 comprising both the seal sleeve/cuff 42 and the material48 can facilitate easier handling during manufacture and production ofthe stent-valve 10.

Various techniques are possible. Purely by way of example, the materialblank 48 may also be obtained from a section of a cardiac valvuloplastyballoon. Referring to FIG. 3 d, the blank 48 may be manipulated while intubular form. For example, mandrels 52 may be inserted into both theelongate tube 46 and the tubular blank 48. By a combination of heat andpressure (indicated by arrows 54), the tubes 46 and 48 may be fusedtogether along an elongate line of attachment 56. Thereafter, themandrels 52 are withdrawn, and the tubular blank 48 may be cut along aline 58 to define a planar section of material for the outer skirt 32.

To facilitate suturing the material 48 to the stent, the material 48 mayalternatively be, or comprise, a fabric. For example, the material maycomprise a film laminated to a fabric. The fabric may be laminated overthe entire area of the film or merely in one of more zones intended tobe sutured. The fabric may be easier than film to suture without risk ofcrack propagation. The presence of fabric in a laminate can alsostabilize the laminate against crack propagation when a suture hole ismade through the laminate. The fabric may be absent in the zone intendedfor, or substantially in register with the seal 40. The absence offabric at this region may enable the material 48 to be thinner at theseal 40, to achieve a compact skirt and seal arrangement suitable forcrimping.

Referring to FIG. 3 e, and whether or not the tube 46 is a separateitem, or attached to material 48 as sub-assembly 50, the swellablematerial 44 may be placed into the interior of the elongate tube 46. Theswellable material 44 may be substantially smaller (e.g., shorter) thanthe tube 46, but be able to swell significantly upon contact with blood,to distend the sleeve/cuff 42 substantially around its periphery. Theswellable material 44 may occupy only a portion of the circumferentiallength of the cuff, for example, optionally not more than about 75%,optionally not more than about 60%, optionally not more than about 50%,optionally not more than about 40%, optionally not more than about 30%,optionally not more than about 25%, optionally not more than about 20%.Optionally, the ends of the elongate tube 46 are each sealed to closethe interior space of the tube 46 with the swellable material 44 captivetherewithin. The ends may, for example, be sealed closed by welding,fusion, or adhesive.

Referring to FIG. 3 f, the sub-assembly 50 (if used) may be bent into atubular form, and attached to the stent 12. In some embodiments, thesub-assembly 50 is attached to the stent in sheet form, by wrapping thesub-assembly 50 around the stent 12. Alternatively, (FIG. 3 g), thesub-assembly may be first secured in a tubular form, and the tubularform attached to the stent 12. For example, the ends of the sub-assemblymay be partly overlapped and welded together, to define a lapped join.The weld may seal closed the ends of the sleeve/cuff 42 (tubing 46). Theweld may be clear of the swellable material within the sleeve/cuff 42.The tubular sub-assembly 50 may have a conical shape to match thecontour of the lower portion of the stent 12. The tubular assembly 50may have a zig-zag edge 50 a to match the peripheral edge at one end(e.g. inlet end) of the stent. For example, the zig-zag edge 50 a may becut and/or trimmed after assembly to the stent 12.

In either case, the sub-assembly 50 may be secured to the stent 12 bysutures 60. Optionally, the sutures 60 pass only through the material ofthe outer skirt 32, and do not penetrate the material of the sleeve/cuff42. The outer skirt 32 may act as the means for securing the sleeve/cuff42 to the stent 12 without compromising the tubular integrity of thesleeve/cuff 42.

As can be seen in FIG. 3 f, the elongate tube 46 is bent into a toroidshape around, or to match, the stent 12. The toroid shape may be aclosed-loop toroid. Alternatively, the toroid shape may be partial loop,a split-loop, or a helical shape, for example. In some embodiments, theends of the tube 46 are not sealed independently, but are sealedtogether to communicate with each other to define a circumferentiallycontinuous hollow space across the join. However, in other embodiments,the ends of the tube 46 may be sealed closed to define a non-continuousinterior across the join.

Referring to FIG. 4, the sleeve/cuff 42 may carry or comprise adiffusion barrier layer 62. For example, the sleeve/cuff material maycomprise a laminate of (i) plastics film 64, and (ii) the diffusionbarrier layer 62. The diffusion barrier layer 62 may serve to preventdiffusion of liquid, or other fluid, through the sleeve/cuff wallmaterial. As explained later below, the stent-valve 10 may be immersedin liquid or other fluid during manufacture (e.g. during sterilization)and/or during storage when packaged ready for use. The diffusion barrierlayer 62 can substantially prevent any trace of liquid diffusing throughthe sleeve/cuff wall, even though the plastics film 64 may be very thin.

In some embodiments, the diffusion barrier layer 62 is a metal ormetal-compound. The diffusion barrier layer 62 may, for example, bedeposited by plasma vapour deposition. The diffusion barrier layer 62may have a thickness of less than 100 nm, optionally less than 50 nm,optionally less than 10 nm. The thickness of the diffusion barrier layer62 may be exaggerated in FIG. 4. The diffusion barrier layer 62 mayoptionally be provided in a non-exterior-surface portion of thesleeve/cuff wall. For example, the diffusion barrier layer 62 may beprovided on an interior face of the sleeve/cuff 42 (as shown in FIG. 4),or it may be provided as a non-surface portion of the laminate. Avoidingplacing the diffusion barrier layer 62 on the exterior face of thesleeve/cuff 42 may reduce the risk of damage to the integrity of thediffusion barrier layer 62, for example, during subsequent handling andproduction of the stent-valve.

When the diffusion barrier layer 62 is formed on a sleeve/cuff 42 thathas an integral tubular structure, plasma vapour deposition may, forexample, be used to deposit the diffusion barrier layer in the hollowspace of the sleeve/cuff 42, on the interior face of the sleeve/cuff 42.The diffusion barrier layer 62 may be deposited after the attachment ofthe sleeve/cuff 42 (or the tube 46) to the material 48 for the outerskirt 32, to avoid risk of damage to the diffusion barrier layer duringattachment of the sleeve/cuff 42 or tube 46 to the material 48.

Alternatively, the exterior face of the sleeve/cuff 42 or tube 46 may becoated with the diffusion barrier layer material, and a furtherprotective coating (not shown) applied over the exposed face of thediffusion barrier layer, to complete the laminate.

In either case, the tube 46 may act as a structural substrate of theresulting laminate, providing the integral tubular structure of thesleeve/cuff 42. Also, in either case, the diffusion barrier layer 62 maybe an integral part of the stent-valve 10 that remains in place and isnot removed at implantation.

Referring to FIG. 5, a method of production of the stent-valve 10 maygenerally comprise one or more of the steps of:

Step 70: providing the stent 12;

Step 72: providing a prosthetic valve 14 (optionally attached to theinner skirt 30);

Step 74: providing the seal 40 (for example, the sub-assembly 50including the sleeve/cuff 42 containing the swellable material, andoptionally the material 48 for the outer skirt 32);

Step 76: assembling the valve 14 and the seal 40 to the stent 12, forexample, using sutures to secure the valve 14 within the stent, and tosecure the sub-assembly around an exterior portion of the stent 12. Thisstep may be omitted during production if the seal 40 (or at least acomponent) is provided as a separate item from the stent-valve 10.

Step 78: sterilizing the assembled stent-valve 10;

Step 80: placing the assembled stent-valve 10 into packaging forstorage; and

Optionally step 82: sterilizing the seal 40 using a sterilizationprocess different from step 78.

The step 78 of sterilizing the assembled stent-valve 10 may be performedby contacting the stent-valve 10 with a sterilization fluid, forsterilizing portions of the stent-valve contacted by the fluid. Thefluid may, for example, be a liquid. Alternatively, the fluid may be agas, or a liquid/gas combination. The sterilization fluid may be, orcomprise a component, toxic to the human blood-stream. For example, thefluid may be intended to be rinsed or otherwise cleaned from thestent-valve prior to implantation. An example sterilization liquidcomprises an aldehyde, for example, glutaraldehyde. The liquid may be anaqueous solution. Step 78 may optionally comprise heating thesterilization liquid to above room temperature, optionally above bodytemperature, optionally at least about 40° C., optionally at least about50° C. Heating the sterilization liquid may enhance efficacy and/orspeed of sterilization.

During step 78, the sleeve/cuff 42 prevents the sterilizing fluid fromcontaminating the swellable material 44, in the case that the seal 40 isintegral with the stent-valve 10. As explained previously, the swellablematerial 44 may swell as a result of absorption of liquid. Toxiccontamination of the swellable material 44 may make it difficult orimpossible to remove the toxic liquid if chemically absorbed by theswellable material 44. Toxic contamination of the swellable material 44may render the stent-valve less appropriate for implantation, and insome cases unimplantable. The sleeve/cuff 42 may prevent suchcontamination (for example, even if a sterilization liquid is heated).If used, the diffusion barrier layer 62 may further enhance theprotective properties of the sleeve/cuff 42 in preventing any liquidfrom diffusing through the sleeve/cuff into the space used for theswellable material.

Steps 78 and 80 may be carried out in either order, or at least partlyat the same time. For example, in some embodiments, at step 80, thestent-valve 10 may be placed into its final packaging and immersed inliquid. The stent-valve may be sterilized in its final packaging, usingthe same liquid. Such a technique may be referred to as “terminalsterilization”. In other embodiments, the stent-valve 10 may besterilized by immersion in a first liquid (step 78), and subsequentlytransferred to a second liquid or storage liquid (step 80). The storageliquid may be similar to the sterilization liquid, and may be orcomprise a component that is toxic to the human blood stream. In suchcase, provision of the sleeve/cuff 42 (and optionally the diffusionbarrier layer 62) protects the swellable material against toxiccontamination. The stent-valve 10 may be stored in the storage liquidfor an extended period of time. The sleeve/cuff 42 may be configured toresist penetration and/or diffusion of the storage liquid to theinterior space of the cuff, for a period of at least 1 month, optionallyat least 6 months, optionally at least 1 year.

Step 82 may be an optional separate step of sterilizing the seal 40,especially the interior of the sleeve/cuff 42. When a fluid-basedsterilization technique may be used for step 78, such a technique shouldnot be used for the interior of the seal 40 because, as explained above,it may result in contamination of the swellable material 44. Instead, insome embodiments, a different non-fluid-contact sterilization techniquemay be used, for example, using radiation sterilization. Step 82 may becarried out at any suitable stage of the production process. In someembodiments, step 82 may be carried out as part of step 74. For example,the sub-assembly 50 may be sterilized so that it is provided at step 74with the sleeve/cuff 42 sterile (or at least having a sterile interior).Alternatively, step 82 may be carried out at any stage after step 76.

Referring to FIG. 6, a method of preparing the stent-valve 10 ready forimplantation may comprise one or more of the following steps (any ofwhich, and optionally all of which, may be carried out outside the bodyof the patient to be implanted):

Step 90: providing the stent-valve 10 in a storage liquid, for example,as explained above;

Step 92: rinsing the stent-valve 10 to clean the storage liquid off thestent-valve 10. During step 92, the liquid-tight property of thesleeve/cuff 42 prevents liquid contact with the swellable material 44.This permits thorough rinsing of the stent-valve 10 desirable to removesubstantially all of the storage liquid.

Step 94: after step 92, exposing the swellable material 44 to permitcontact with liquid; and

Step 96: after step 92, compressing the stent-valve 10 and/or loadingthe stent-valve 10 into a delivery apparatus 98 (FIG. 8).

Steps 94 and 96 may be carried out in either order or at least partly atthe same time as each other.

In some embodiments, step 96 may comprise the step of piercing thesleeve/cuff 42 using a piercing tool 100, to penetrate the sleeve/cuffmaterial and create one or more liquid-admitting punctures in thesleeve/cuff 42. Piercing the sleeve/cuff 42 may leave the material ofthe sleeve/cuff 42 in place. For example, if used, a diffusion barrierlayer may remain in place on the stent-valve 10, even afterimplantation. The punctures created in the sleeve/cuff 42 may passthrough the diffusion barrier layer. An example piercing tool 100 isillustrated in FIG. 7. The piercing tool 100 may comprise at least onesharp pin 102 (or other sharp projection), and a handle portion 104 forenabling manual manipulation of the tool. The pin 102 may be dimensionedsuch that it can safely penetrate the sleeve/cuff 42 without reachingthrough to the interior of the stent 12, and valve 14. Damage to thevalve 14 can be prevented. In some embodiments, a face or flange 106 ofthe handle portion 104 may act as an abutment that bears against thesleeve/cuff 42 surface to limit the depth of penetration, or anotherform of “stop” may be provided. In other embodiments, the piercing toolmay comprise a roller having a surface on which is formed at least onesharp pin (preferably plural pins). In use, the roller is rolled on thesurface to be pierced, and the punctures are created as the rollerrotates on that surface.

Optionally, the step of piercing the sleeve/cuff 42 may include piercingthe sleeve/cuff 42 at one or more positions that are clear of thelocation of the swellable material 44 within the cuff. Piercing thesleeve/cuff 42 away from the swellable material 44 may avoid risk ofphysical damage to a swellable material component. In some embodiments,the sleeve/cuff 42 may be transparent, or translucent, and the swellablematerial 44 may have a color (e.g. a distinctive color) to enable thelocation of the swellable material inside the sleeve/cuff 42 to beidentified. This can help the medical practitioner if it is desired topierce the sleeve/cuff 42 at positions clear of the location of theswellable material 44.

Additionally or alternatively, whether or not the sleeve/cuff 42 is tobe pierced at positions clear of the swellable material 44, thesleeve/cuff 42 may comprise indicia to indicate suitable positions onthe sleeve/cuff 42 at which to pierce/penetrate the sleeve/cuffmaterial, to create the liquid-admitting punctures.

Generally, the ability to complete the exposure step 94 prior tointroduction into the patient's body can avoid any need to rely on anexposure mechanism that is activated as part of the implantationprocedure once inside the body, for example, the pressure responsiverupturing capsules described in the aforementioned US-A-2007/0060998 andWO-A-2010/083558. This can reduce the risk of complication should, insome cases, such an exposure mechanism malfunction and fail to operatecorrectly at the time of implantation and once already in the body,where the possibility of further intervention may already be limited.

In some embodiments, step 96 may comprise using a compressing tool (suchas one or more funnel shaped tubes, not shown) through which thestent-valve 10 is advanced in order to compress the stent-valve 10 toits compressed configuration. The stent valve 10 may be coupled to,and/or loaded within a constraining sheath 106 of, the delivery catheter98. The constraining sheath 106 may constrain the stent-valve 10 in thecompressed configuration suitable for introduction into the patient viaminimally invasive surgery or a percutaneous procedure.

In some embodiments, step 96 may be carried out at least partly whilecontacting the stent-valve 10 with liquid, for example, at least partlyimmersing the stent-valve in liquid. The liquid may be water or saline.The liquid may be cold, for example, at a temperature less than roomtemperature (for example, cold water or cold saline). For example,carrying out the compressing step in cold liquid may make the stent 12more supple and easier to compress. Additionally or alternatively, thecontainment sheath 106 may be flushed or at least partly filled withliquid to purge air from the containment sheath 106, prior tointroduction into a patient's body.

In some embodiments, especially where step 96 is carried out at leastpartly while contacting the stent-valve 10 with liquid, it may bedecided to carry out step 94 after the stent-valve 10 (or at least aportion of the stent-valve 10 carrying the seal 40) is constrained in acompressed condition by the constraining sheath 106. Such a techniquecan (i) permit at least partial exposure of the swellable material 44 toliquid to at least partly wet or hydrate the swellable material 44 priorto introduction into the patient's body, and (ii) prevent the seal 40from swelling prematurely, even though the swellable material 44 isexposed to liquid.

Wetting or hydrating the swellable material 44, at least partly, priorto introduction into the body may in some cases be beneficial to enablemore efficient swelling of the material 44, and therefore of the seal 40and/or sleeve/cuff 42, when the stent-valve 10 is implanted. It canavoid the need for the seal 40 to have to become wetted or to hydrateonly on implantation. For example, speed of wetting and/or hydrationand/or swelling may in some cases be a consideration if theliquid-admitting apertures (e.g. punctures) in the sleeve/cuff 42 arerelatively small and/or if a relatively “slow” wetting and/or hydratingand/or swelling material 44 is used within the sleeve/cuff 42.

Additionally or alternatively, exposing the swellable material 44 onlyrelatively late in the preparation procedure may combine (i) theadvantage of being able to perform the exposure step 94 outside thepatient's body (to avoid having to rely, as mentioned above, on anexposure mechanism that is activated as part of the implantationprocedure once in the body), while (ii) limiting the amount of timeduring which the swellable material (44) is exposed to liquid prior tothe implantation. Exposure during an excessive period of time might, insome cases and depending on the materials used, be counterproductive tothe use as a dynamically swelling seal. In some embodiments, theswellable material 44 might be exposed to liquid outside the patient'sbody, for a time duration of: optionally not more than about 1 hour;optionally not more than about 30 minutes; optionally not more thanabout 20 minutes; optionally not more than about 15 minutes; optionallynot more than about 10 minutes; optionally not more than about 9minutes; optionally not more than about 8 minutes; optionally not morethan about 7 minutes; optionally not more than about 6 minutes;optionally not more than about 5 minutes; optionally not more than about4 minutes; optionally not more than about 3 minutes; optionally not morethan about 2 minutes; optionally not more than about 1 minute.

FIG. 8 illustrates a portion of a delivery catheter 98, including acontainment region 108 for the stent-valve 10 (indicated schematicallyin its compressed configuration by broken lines), and a constrainingsheath 106. The delivery catheter 98 is illustrated in a conditionoptionally outside the patient's body, but in which the stent-valve 10is loaded, and the delivery catheter 98 may be ready for introductioninto the patient's body. The constraining sheath 106 may be translatablebetween a closed condition (as shown) in which the sheath 106substantially constrains the stent-valve 10 in its compressedconfiguration, ready for introduction into the patient's body anddelivery to the implantation site, and an open position (not shown) inwhich the sheath is translated in a direction (e.g. as illustrated byarrow 110 towards a handle portion 114, but optionally in the oppositedirection away from the handle portion 114) to expose the stent-valve 10for expansion to the operative configuration for implantation. Thedelivery catheter 98 may further comprise a flushing port 112 (which mayoptionally be at the handle portion 114 or handle-end of the deliverycatheter). The flushing port 112 permits introduction of a liquid 116(e.g. saline) for filling at least the containment region 108, and forpurging trapped air from the containment region 108. The stent-valve 10is immersed in the liquid 116 inside the containment sheath 106.

The sheath 106 may comprise a plurality of guide apertures 118 which, inthe closed condition of the sheath 106, align with, or overlap orotherwise become in register with, the sleeve/cuff 42 and/or seal 40.The guide apertures 112 are intended to permit insertion of the pin 102of the piercing tool 100, in order to create liquid-admitting puncturesin the cuff, as described earlier above. The liquid-admitting puncturesmay be formed before, or after, or during, the introduction of liquid116 into the containment region 108. The punctures may cause the liquid116 to come into contact with the swellable material 44 of the seal 40.However, the constraining sheath 106 can prevent substantial expansionof the seal 40 until the moment of implantation.

FIG. 9 illustrates an alternative version of the delivery catheter 98comprising plural sheaths 106 a and 106 b. The sheaths may meetsubstantially end to end (as shown), or they may be at least partiallyoverlapping (not shown). In a similar manner to that described above, atleast one of the sheaths 106 a and 106 b may comprise guide aperturesintended to permit insertion of the pin 102 of the piercing tool 100 topenetrate and pierce the sleeve/cuff 42 of the stent-valve 10.Alternatively (as shown), a small gap 118 at the interface between thetwo sheaths 106 a and 106 b may provide the guide aperture for insertionof the piercing tool.

Referring to FIG. 10, a method of implanting the stent-valve 10 maycomprise one or more of the following steps:

Step 120: providing the stent-valve 10 in its compressed configurationready for introduction into a patient's body. Optionally this step mayinclude the preparation steps of FIG. 6 and/or apparatus of any of FIGS.7 to 9;

Step 122: introducing the stent-valve 10 in its compressed configurationinto the patient's body, and advancing the stent-valve to a desiredimplantation site. By way of example, if the sleeve/cuff 42 may includea diffusion barrier layer 62, then step 122 may include introducing thestent-valve 10 with the diffusion barrier layer 62 still in place on thesleeve/cuff 42. Optionally, the sleeve/cuff 42 may have been pierced atonce or more positions to create liquid-admitting punctures in thesleeve/cuff 42 that pass through the diffusion barrier layer 62.

Step 124: causing the stent-valve 10 to expand at the implantation site,from the compressed configuration to the operative configuration. If thestent 12 is of a self-expanding type, the expansion may be caused byremoving a constraining sheath (e.g. sheath 106), in order to allow thestent 12 to self-expand towards the operative configuration.Additionally or alternatively, if the stent 12 is of a type in whichmanipulation of the stent-valve 10 is used to cause the stent-valve 10to adopt its operative configuration, step 124 may include causing suchmanipulation, for example, by inflating an expansion balloon and/orforeshortening the stent 12 to a foreshortened state.

Step 126: observing one or more characteristics of the operativestent-valve. For example, one such characteristic may be the extent ofpara-valve leakage of blood. Such a characteristic may be observed usingany suitable technique, for example, Doppler-effect ultrasound.Additionally or alternatively, the implantation position, and/or theextent to which the stent has expanded, and/or the pressure gradientthrough the valve, may be observed.

Step 128: in dependence of the result of the observation in step 126,performing post-implantation balloon expansion of the stent-valve 10.For example, if the observation of step 126 indicates that a para-valveleakage condition is not acceptable, and/or that the stent has notexpanded as much as desired, and/or that the pressure gradient isundesirably high, a balloon catheter may be inserted into the interiorof stent 12, and expanded to improve the seating/expansion of the stent12 within the native anatomy at the implantation site. If theobservation at step 126 indicates that a para-valve leakage conditionand/or other conditions is acceptable (for example, there is nosubstantial leakage), then step 128 may be skipped.

Step 128 may be performed after a time interval sufficient to permitswelling of the seal 40 to adapt to the native anatomy. For example, thetime interval may be at least about 30 seconds, optionally at leastabout 40 seconds, optionally at least about 50 seconds, optionally atleast about 1 minute, optionally at least about 75 seconds, optionallyat least about 90 seconds, optionally at least about 105 seconds,optionally at least about 2 minutes, optionally at least abouttwo-and-a-half minutes, optionally at least about 3 minutes, optionallyat least about three-and-a-half minutes, optionally at least about 4minutes, optionally at least about four-and-a-half minutes, optionallyat least about 5 minutes. Additionally or alternatively, the timeinterval may optionally be not substantially more than about 10 minutes,optionally not substantially more than about 9 minutes, optionally notsubstantially more than about 8 minutes, optionally not substantiallymore than about 7 minutes, optionally not substantially more than about6 minutes, optionally not substantially more than about 5 minutes,optionally not substantially more than about 4 minutes, optionally notsubstantially more than about 3 minutes, optionally not substantiallymore than about 2 minutes, optionally not substantially more than about1 minute.

It may not be intuitive to consider carrying out post-implantationballoon-expansion of a stent-valve that includes a swellable seal 40,because it might ordinarily be expected that the seal 40 will be able toseal against the anatomy automatically. However, steps 126 and 128 maypermit the medical practitioner to determine, at least prior tocompletion of the medical procedure and while the patient is still in acondition ready for intervention, the efficacy of the seal 40 in sealingbetween the stent-valve 10 and the surrounding local anatomical tissue.If the seal 40 is determined not to be sufficiently effective, then step128 may be used to increase the seating of the stent-valve 10 within thelocal anatomy, and the associated sealing effect of the seal 40. Steps126 and 128 may be performed once, or repeated two or more times, asdesired, for example, until para-valve leakage is reduced to anacceptable condition.

As explained earlier above, the seal 40 may be configured to be able towithstand a post-implantation balloon-expansion procedure, without riskof bursting.

Referring to FIGS. 11 and 12, alternative structures of seal 40 areillustrated. The seal 42 comprises sleeve/cuff 42 containing swellablematerial 44. These embodiments may use any of the details describedabove for the sleeve/cuff 42 of preceding embodiments. In FIG. 11, thesleeve/cuff 42 may comprise an integral tubular structure, providingequivalent advantages to those discussed above. In FIG. 12, thesleeve/cuff 42 may comprise an envelope formed of one or more walls ofmaterial welded together along one or more peripheries.

However formed, the sleeve/cuff 42 may comprise a single wall, or thesleeve/cuff may comprise plural walls nested one behind, or within,another. At least one wall may comprise a single layer of material,and/or at least one wall may comprise plural layers of material (e.g. amulti-layered wall and/or a laminate).

The sleeve and/or cuff 42, or at least a wall or layer thereof, maycomprise a region 200 that is permeable or at least semi-permeable toliquid. The permeable/semi-permeable region may be configured to (i)allow communication of blood components therethrough (for example, intothe interior of the sleeve/cuff 42 to cause the swellable material 44 toswell), and/or (ii) obstruct passage therethrough of blood emboli (forexample, to substantially prevent escape into the blood stream of anyemboli that may form within the sleeve/cuff 42), and/or (iii) obstructpassage therethrough of swellable material 44 particles (for example, tosubstantially prevent escape into the blood stream of any looseparticles of the swellable material 44).

The permeable/semi-permeable region 200 may have pores (e.g.perforations 202 of FIG. 13). The pore size (e.g. average pore size)may, for example, be not substantially greater than about 0.2 mmOptionally, the pore size may be not substantially greater than about0.15 mm, optionally not substantially greater than about 0.12 mm,optionally not substantially greater than about 0.11 mm, optionally notsubstantially greater than about 0.1 mm, optionally about 0.1 mm.

In some embodiments, the permeable/semi-permeable region 200 may extendover only a portion of the sleeve/cuff 42, and/or over only a portion ofa wall of the sleeve/cuff 42, and/or a layer of the sleeve/cuff 42.

The permeable/semi-permeable region 200 may comprise perforated film,for example, laser perforated film.

The (e.g. laser) perforated film may be a monolayer film, or a laminateof two or more layers. The pore size of the (e.g. laser) perforated filmmay optionally have a variation of less than 20% from an average poresize, optionally less than 15% from an average pore size, optionallyless than 10% from an average pore size, optionally less than 5% from anaverage pore size.

In some embodiments, the (e.g. laser) perforated film may have athickness of not substantially greater than 0.05 mm. Use of such a thinfilm can contribute to achieving a compact sleeve/cuff 42 for enablingthe stent-valve to achieve a desirably small size for delivery bycatheterization. Optionally the film thickness is not substantiallygreater than about 0.045 mm, optionally not substantially greater thanabout 0.04 mm, optionally not substantially greater than about 0.035 mm,optionally not substantially greater than about 0.03 mm, optionally notsubstantially greater than about 0.025 mm, optionally not substantiallygreater than about 0.02 mm, optionally not substantially greater thanabout 0.015 mm, optionally not substantially greater than about 0.01 mm,optionally not substantially greater than about 0.005 mm. In someembodiments, the film thickness may be between about 0.005 mm and about0.015 mm, optionally between about 0.005 mm and about 0.01 mm.

In some embodiments, the (e.g. laser) perforated film may have astrength (e.g. linear tensile strength) at least 50% of the filmstrength prior to laser perforation, optionally at least 60% of thestrength prior to laser perforation, optionally at least 70% of thestrength prior to laser perforation, optionally at least 80% of thestrength prior to laser perforation, optionally at least 90% of thestrength prior to laser perforation. Such characteristics can contributeto a strong film even with thin film thickness.

Referring to FIG. 13, in some embodiments, the pores 202 (or at least amajority thereof) in the (e.g. laser) perforated film are substantiallyround and/or have a cauterized perimeter 204 and/or have a raised margin206 around their perimeter. Such a feature or features may contributeindividually or in combination to film strength even with thin filmthickness. A round pore shape can avoid sharp corners in the peripheralshape that could be points of stress concentration or lead to outwardcrack propagation. Cauterization of the material around the perimeter204 of the pore may also advantageously reduce risk of outward crackpropagation. A raised margin 206 of material around the pore perimetermay also provide additional material, and hence strength, surroundingthe open area of the pore.

Referring to FIG. 14, the permeable/semi-permeable region 200 may extendsubstantially over the entire surface of the sleeve/cuff 42, or theregion 200 may be positioned in one or more specific zones, leavingother zones substantially non-perforated.

In some embodiments, the permeable/semi-permeable region may be disposedin one or more of:

A zone 210 facing substantially or at least partly towards thestent-valve blood outlet. When the valve 14 closes in use, bloodback-pressure may tend to urge blood towards the seal 40 from the outletdirection, and placing the permeable region in zone 210 may provide goodcommunication of blood to the seal for causing the swellable material 44to swell; and/or

A zone 212 facing substantially or at least partly towards thestent-valve blood flow inlet. Blood passing dynamically through thestent-valve generally approaches the stent-valve from the inletdirection, and placing the permeable region in zone 121 may provide goodblood communication into the seal; and/or

A zone 214 facing substantially or at least partly radially outwardlyand/or a zone 216 facing substantially or at least partly radiallyinwardly.

In some embodiments in which at least a wall or layer of the cuff/sleeve42 having the perforations is, in use, able to directly contact thesurrounding native tissue, the permeable region may optionally beconfigured to be outside of the zone 214. Such an arrangement can avoidor reduce any risk that hard calcification 217 of the native tissuecould enlarge a perforation by direct contact therewith, or otherwisedamage the perforated region 200.

Referring to FIG. 15, in some embodiments, the cuff/sleeve 42 mayfurther comprise an impermeable layer or wall 218 extending partly orentirely around the periphery of the cuff/sleeve 42 when viewed incross-section, and/or partly or entirely in the circumferentialdirection of the stent-valve 10.

Referring to FIG. 16, in some embodiments, at least a component of theseal 40 may be provided as a separate item from the stent-valve 10. Theat least a component of the seal 40 may be intended to be mounted orfitted or introduced to the stent-valve 10 as part of a pre-implantationpreparation process, e.g. after rinsing the stent-valve 10 clean of anystorage solution. In the embodiment of FIG. 16, the seal 40 is providedseparately, and is intended to be mounted to the stent-valve 10 as partof the pre-implantation preparation process.

The seal 40 may comprise the swellable material 44 and a cuff/sleeve 42.The cuff/sleeve 42 may comprise a permeable or semi-permeable region200. The seal 40 may be generally elongate. The seal 40 may be providedin its own sterilized container 220, e.g. a pouch. The pouch may be atear-open pouch. The seal 40 may have been sterilized using any suitableprocess, for example, radiation sterilization. The seal 40 may have beensterilized in its container 220.

In some embodiments, the stent-valve 10 comprises a dedicated sealaccommodation region 221 to which the seal is mountable. The sealaccommodation region 221 may be provided as part of an outer skirt 32 ofthe stent-valve 10.

The seal accommodation region 221 may be or comprise a sealaccommodation channel 222. In some embodiments, the seal accommodationchannel may be discontinuous. Referring to FIG. 17, a discontinuouschannel 222 may be provided by a series of spaced apart loops 224, forexample, similar to clothing belt loops. The number of loops 224, andthe circumferential length of each loop 224, may be selected to providea desired mark/space ratio (e.g. closed-area/open-area ratio). Themark/space ratio may optionally be about 1. Additionally oralternatively, the ratio may be less than 1, optionally less than about0.75, optionally less than about 0.5, optionally less than about 0.25.Additionally or alternatively, the ratio may at least about 1,optionally at least about 1.25, optionally at least about 1.5,optionally at least about 1.75, optionally at least about 2, optionallyat least about 2.5, optionally at least about 3.

Referring to FIG. 18, a substantially continuous accommodation channel222 may be provided by an (e.g. annular) flap 226 of material extendingsubstantially continuously in a circumferential direction around thestent-valve 10. The flap 226 may define a channel that is open in onedirection, for example, open in a direction facing towards the bloodoutlet end of the stent-valve in FIG. 18, and/or open in an oppositedirection facing towards the blood inlet end of the stent-valve (notshown). Referring to FIG. 19, the flap 226 may further comprise a seriesof spaced apart extensions 228 that couple to the stent-valve, to definea series of clearances between adjacent extensions 228 instead of acontinuously open region. The extensions 228 may define a castellatedshape. Referring to FIG. 20, an edge 230 of the flap may have ascalloped shape between the extensions 228 to define a curved shape ofthe clearances thereby to avoid abrupt edges.

Alternatively, referring to FIG. 21, a substantially continuousaccommodation channel 222 may be provided by a tube (or an envelope)232. The tube 232 may have an integral tubular structure, providedsimilar advantages to those described previously.

The tube 232 may have communication openings 234 for admitting blood tothe interior of the channel. In the example shown, at least some of theopenings 234 may be arranged facing substantially or at least partlytowards the stent-valve blood outlet. When the valve 14 closes in use,blood back-pressure may tend to urge blood towards the seal 40 from theoutlet direction, and such an arrangement of the openings may providegood communication of blood to the seal 40 for causing the swellablematerial 44 to swell. Additionally or alternatively, at least some ofthe openings 234 may be arranged (not shown) facing substantially or atleast partly towards the stent-valve blood flow inlet. Blood passingdynamically through the stent-valve generally approaches the stent-valvefrom the inlet direction, and such an arrangement of the openings mayprovide good blood communication into the seal 40. Additionally oralternatively, at least some of the openings may arranged (not shown)facing substantially or at least partly radially outwardly and/or facingsubstantially or at least partly radially inwardly.

For similar reasons to those discussed previously in relation to FIG.14, in some embodiments, the openings 234 may be arranged so as not toface substantially radially outwardly. In other words, the radiallyoutward facing portion of the tube 232 may have a substantiallycontinuous surface to shield the seal 40 within the tube 232 from directcontact with hard calcifications of the surrounding native anatomy.

The seal 40 may be loadable or introducible into the channel 222 by anysuitable means. In some embodiments, a loading filament 240 (e.g. madeof medical suture thread) may be pre-laid within the channel 222 along apredefined path, and used as device for pulling or drawing the seal 40into the channel 222. For example, the opposite ends of the thread 240may project outwardly from the channel, for example through openings orclearances previously described, or through additional and/or dedicatedloading apertures (not shown). In order to load the seal 40, one end ofthe filament 240 may be coupled to an end of the seal 40. Pulling on theopposite end of the filament 240 withdraws the filament 240progressively from the channel, at the same time drawing the seal 40into the channel along the predefined path previously occupied by thefilament. The predefined path may extend at least partlycircumferentially around the periphery of the stent-valve, along a pathlength corresponding to at least about 180 degrees, optionally at leastabout 225 degrees, optionally at least about 270 degrees, optionally atleast about 315 degrees, optionally about or at least about 360 degrees.360 degrees corresponds to a complete circumferential path length aroundthe circumference of the stent-valve. The path length may optionally begreater, and correspond, for example, to about or at least about 1.5turns, or optionally to about or at least about 2 turns, or more. Oncethe seal 40 is loaded, the filament 240 (or at least a projectingportion of the filament 240) may be disconnected (e.g. cut) from theseal 40 to leave the seal in place within the channel 222.

Alternatively, referring to FIG. 22, the seal 40 may be adhesivelyattachable to the stent-valve 10. For example, at least one of the seal40 and the seal accommodation region 221 may comprise an adhesiveregion, optionally protected by a respective peelable release sheet. Ifadhesive is provided on only one part (e.g. on the seal 40), the otherpart (e.g. the seal accommodation region 221) may comprise a landingsurface for adhesive attachment by the other part.

Alternatively, referring to FIG. 23, the outer skirt 32 may comprise ahollow band 242 into which the swellable material 44 may be introducedin flowable form, as part of the pre-implantation preparation process.An example flowable swellable material may, for example, be or compriseswellable microspheres, for example, poly(vinyl alcohol-sodium acrylate)copolymer microspheres. In some embodiments, the flowable material maybe injected into the band 242, either directly through the wall of theband, or using a dedicated inlet port 244. The band 242 may represent orcorrespond to a seal accommodation region 221 and/or a sealaccommodation channel 222 in any of the following description.

Referring to FIG. 16, if the stent geometry previously described forFIG. 1 is used, the seal accommodation region 221 (e.g. sealaccommodation channel 222) may be positioned to be clear of the uppercrown 18 in order not to interfere with blood through the upper crown tocoronary arteries (e.g. in the case of a stent-valve for the aorticvalve position).

Additionally or alternatively, if the stent geometry previouslydescribed for FIG. 1 is used (referring also FIG. 16), the sealaccommodation region 221 (e.g. seal accommodation channel 222) may bepositioned only between the upper crown 18 and the upper apexes 16 b ofthe lower and/or inlet extremity. For example, the seal accommodationregion 221 does not extend to occupy space between the upper apexes 16 band the lower apexes 16 a of the extremity. Positioning the seal 40clear of the lower apexes 16 a can reduce the bulk of material at thelower/inlet extremity of the stent, and facilitate crimping.

Referring to FIGS. 16 and 24, the outer skirt 32 may comprise at leastone attachment zone 250 positioned axially above and/or below the sealaccommodation region 221. The skirt 32 may be secured to the stent 12and/or to the inner skirt 30 by the at least one attachment zone 250,such that the attachment does not interfere with, or increase thethickness of, the seal accommodation region 221. The skirt 32 may beattached by any suitable means, for example, suturing, welding, fusionor adhesive. In FIG. 16, suturing is indicating by a broken line. Insome embodiments, two attachment zones 250 are provided, one above andone below the seal accommodation region 221. The lower periphery of theouter skirt 32 (and optionally of one of the attachment zones 250), mayhave a zig-zag shape to match a zig-zag shape of a lower and/or inletextremity of the lower portion of the stent 12.

Referring to FIG. 25, the outer skirt may comprise a sheet of filmmaterial 252. The film material 252 may provide both the at least oneattachment zone 250, and a support for or at the seal accommodationregion 221, (indicated schematically in FIGS. 25-28). Alternatively,referring to FIGS. 26-28, the outer skirt 32 may comprise fabricmaterial 254 at least at the one or more attachment zones 250. Fabricmaterial may be easier to attach by means of suturing, with less risk tothe integrity of the material than if a film is sutured. A polymer filmmaterial, and especially a crystalline polymer film material (such asPEEK, for example), may be vulnerable to outward crack propagation fromsuture holes, whereas a fabric made of the same material may much lessvulnerable. FIG. 26 illustrates a hybrid skirt that comprises onlyfabric 254 for the attachment zones 250, and only film 252 at the sealaccommodation region 221. The fabric and film regions may be weldedtogether, for example. FIG. 27 illustrates a modified hybrid skirt inwhich the film 252 extends substantially the entire axial height of theskirt, and fabric material 254 is laminated at the attachment zones 250.The fabric material 254 can support the film 252 to provide resistanceto crack propagation. The fabric material 254 may be heat sealed orfused to the film in order to form the laminate. FIG. 28 illustrates afurther modified hybrid skirt in which the fabric and film aresubstantially coextensive and form a skirt consisting of laminate oversubstantially its entire axial height.

Referring to FIG. 29, a further example of separate seal 40 isillustrated. The seal 40 comprises a saddle or harness 258 that isclipped and/or hooked and/or threaded to the stent 12, for example, byattaching to the projecting apexes or valleys of the upper crown 18 andlower portion or crown 16.

Referring to FIG. 30, a method of using and/or preparing a stent-valve10 (especially as described in any of the embodiments of FIGS. 11 to 29)is illustrated.

At step 260 and 262, a stent-valve 10 and at least a component for aseal 40, are provided as separate items. The separate items mayoptionally be provided as part of a kit (step 264), but nevertheless theat least a component of the seal 40 may be non-integral with thestent-valve 10. Step 260 may comprise providing the stent-valve immersedin a storage and/or sterilization solution, as described above. Step 262may comprise providing the at least a component for a seal in a drysterilized state, such as in a sterilized pouch. By providing the atleast a component of the seal separately, there is substantially no riskthat the seal might be wetted or contaminated by the storage solution inwhich the stent-valve is stored. A storage compartment or container forthe seal may be outside a storage compartment or container for thestent-valve.

At step 266, the stent-valve 10 may be rinsed to remove substantiallytraces of the storage solution. Step 266 may comprise placing thestent-valve into a bath of a rinsing solution, for example, water orsaline. Step 266 may comprise placing the stent-valve into one or moresuccessive baths to provide a multi-stage rinse.

At step 268, the at least a component of the seal may be mounted to, orintroduced to or into the stent valve 10. For example, the seal may beloaded into a seal accommodation channel, or the seal may be attachedadhesively, or clipped or hooked to the stent-valve. Alternatively, aflowable swelling material may be injected into a seal band.

At step 270, the assembled stent-valve and seal is exposed to liquidwhile outside the patient's body (e.g. similar to step 94 describedpreviously), and at step 272 the assembled stent-valve is compressedand/or loaded into a delivery catheter (e.g. similar to step 96described previously). As previously, steps 270 and 272 may be carriedout substantially at the same time, or one of the steps may be startedbefore the other in either order, or the steps may be carried outseparately in either order.

One loaded into the delivery catheter, the stent-valve 10 may beimplanted using a method, for example, similar or the same as that ofFIG. 10.

Although the foregoing description has described the embodiments interms of a stent-valve 10, it will be appreciated that many of the sametechniques may be applied to other (e.g. stented) prostheses.

It is emphasized that the foregoing description of preferred embodimentsdoes not limit the scope of the invention, and that many alternatives,modifications, and improvements may be made within the scope and/orprinciples of the invention.

1-84. (canceled)
 85. A stent-valve for transcatheter implantation toreplace a cardiac valve, the stent-valve being compressible to acompressed configuration for delivery, and expandable to an operativestate for implantation, the stent-valve comprising a stent, a pluralityof leaflets defining a prosthetic valve, and a seal for sealing againstsurrounding tissue, wherein the seal comprises: a hollow sleeve/cuffarranged to extend in a circumferential direction substantially aroundthe stent and containing swellable material that swells when contactedby blood to distend the hollow cuff, the hollow sleeve/cuff comprisingan integral tubular structure.
 86. The stent-valve of claim 85, whereinthe hollow sleeve/cuff comprises a tubular extrusion or blow moldedtubing.
 87. The stent-valve of claim 85, wherein the hollow sleeve/cuffdefines a hollow toroid shape around the stent, the toroid shape beingclosed-loop or split or helical.
 88. The stent-valve of claim 87,wherein the hollow sleeve/cuff comprises an elongate tubular member bentto define the toroid shape.
 89. The stent-valve of claim 88, wherein theends of the elongate tubular member are joined together to define aclosed-loop toroid shape.
 90. The stent-valve of claim 85, wherein thehollow sleeve/cuff comprises a tubular segment from a valvuloplastyballoon.
 91. The stent-valve of claim 85, wherein the hollow sleeve/cuffcomprises a laminate of (i) plastics film and (ii) a diffusion barrierlayer to obstruct diffusion of liquids from outside the hollowsleeve/cuff to the hollow interior, the diffusion barrier layercomprising metal or a metal compound.
 92. A stent-valve fortranscatheter implantation to replace a cardiac valve, the stent valvebeing compressible to a compressed configuration for delivery, andexpandable to an operative state for implantation, the stent-valvecomprising a stent, a plurality of leaflets defining a prosthetic valve,and a seal for sealing against surrounding tissue, wherein the externalseal comprises: a hollow sleeve/cuff arranged to extend in acircumferential direction substantially around the stent and containingswellable material that swells when contacted by blood to distend thehollow cuff, comprising a laminate of (i) plastics film and (ii) adiffusion barrier layer to obstruct diffusion of liquids from outsidethe hollow sleeve/cuff to the hollow interior, the diffusion barrierlayer comprising a layer comprising metal or a metal compound.
 93. Thestent-valve of claim 92, wherein the diffusion barrier layer is a plasmavapor deposited layer.
 94. The stent-valve of claim 92, wherein thediffusion barrier player is formed (i) on an interior face of the cuff,or (ii) as a non-surface layer of the laminate.
 95. The stent-valve ofclaim 92, wherein the diffusion barrier layer has a thickness of lessthan 100 nm, optionally less than 50 nm, optionally less than 10 nm. 96.The stent-valve of claim 92, wherein the diffusion barrier layer remainsin position on the stent-valve when the valve is implanted.
 97. Thestent-valve of claim 92, wherein the hollow sleeve/cuff is configured towithstand post-implantation balloon expansion of the stent-valve againsta calcified anatomy without substantial loss of structural integrity ofthe hollow cuff.
 98. A stent-valve for transcatheter implantation toreplace a cardiac valve, the stent valve being compressible to acompressed configuration for delivery, and expandable to an operativestate for implantation, the stent-valve comprising a stent, a pluralityof leaflets defining a prosthetic valve, and a seal for sealing againstsurrounding tissue, wherein the external seal comprises: a hollowsleeve/cuff arranged to extend in a circumferential directionsubstantially around the stent and containing swellable material thatswells when contacted by blood to distend the hollow cuff, the hollowsleeve/cuff being configured to withstand post-implantation balloonexpansion of the stent-valve against a calcified anatomy withoutsubstantial loss of structural integrity of the hollow cuff.
 99. Thestent-valve of claim 98, wherein the sleeve/cuff is configured to bemanually pierceable at one or more points to define liquid admittingpunctures permitting liquid entry into the cuff.
 100. The stent-valve ofclaim 98, wherein the sleeve/cuff has one or more liquid admittingpunctures made therein, prior to introduction of the stent-valve intothe body of a patient, for admitting liquid into the seal.
 101. Astent-valve for transcatheter implantation to replace a cardiac valve,the stent valve being compressible to a compressed configuration fordelivery, and expandable to an operative state for implantation, thestent-valve comprising a stent, a plurality of leaflets defining aprosthetic valve, and a seal for sealing against surrounding tissue,wherein the external seal comprises: a hollow sleeve/cuff arranged toextend in a circumferential direction substantially around the stent andcontaining swellable material that swells when contacted by blood todistend the hollow cuff, the hollow sleeve/cuff comprising a film madeof liquid-impermeable material, the sleeve/cuff having one or moreliquid admitting punctures made therein, prior to introduction of thestent-valve into the body of a patient, for admitting liquid into theseal.
 102. The stent-valve of claim 101, wherein the number of puncturesis less than fifty, optionally less than forty, optionally less thanthirty, optionally less than twenty, optionally less than ten.
 103. Thestent-valve of claim 101, wherein the seal further comprises a skirtsecured to the hollow cuff.
 104. The stent-valve of claim 103, whereinthe skirt is secured to the sleeve/cuff by an attachment that does notpuncture the cuff, for example, an attachment selected from: fusion;welding; adhesive.
 105. The stent-valve of claim 103, wherein the skirtis secured to the stent, thereby mounting the sleeve/cuff to the stent.